The present invention relates to a photoaging inhibitor and a skin-care preparation and more particularly to a photoaging inhibitor comprising an aromatic compound derivative of triterpenoid and/or salts thereof and to a skin-care preparation which contains an aromatic compound derivative of triterpenoid and/or salts thereof and is excellent in the skin beautifying effect of preventing and ameliorating wrinkled skins.
Generally, by the term skin aging is meant a physiological phenomenon which involves a physiological aging with getting old and photoaging due to exposure to sunlight (ultraviolet rays) influencing each other. Currently, attention is being paid to relationship between the latter, i.e., photoaging, and wrinkled skin, rough skin, spots, and the like. That is, it has been known that continued exposure to sunlight (ultraviolet rays) increases deep wrinkles in the face or neck and further renders the skin dry and rough, and causes pigment deposition such as spots, freckles, and the like. Therefore, troubles in the skin due to photoaging has become an issue.
Hitherto, in order to prevent the damages to the skin due to ultraviolet rays, cosmetics (sun-screen or sun-protecting cosmetics) containing various ultraviolet absorbents, scattering or shielding agents, such as titanium oxide, zinc oxide, p-methoxycinnamic acid esters, p-aminobenzoic acid esters, and the like, have been developed and put into use. However, it is difficult to protect the skin from abundant exposure to sunlight despite the use of such cosmetics. Further, it has been known that external application of all trans-type retinoic acid is effective as a method of improving the above-described photoaging (see Methods in Enzymology, Vol. 190, p. 352-360 (1990)). However, use of this method is open only to doctors from the viewpoint of safety so that there has been demanded a development of a photoaging inhibitor and skin-care preparations which are highly effective and safe.
Accordingly, in order to meet the above-described demand, there have been used triterpenoids from plant origins, such as ursolic acid and oleanolic acid, or their derivatives such as esters, in photoaging ameliorating agents, cosmetics, externally applied skin agents and the like. However, triterpenes used as raw materials for these substances are very low in their content in plants so that there occur problems that blending them in amounts which assure sufficient effects is expensive and that it is difficult to assure a sufficient supply of them. Therefore, there has been a demand for the development of triterpenoid compounds that can exhibit sufficient effects in small amounts among the triterpenoid compounds which are highly safe, have photoaging preventing and ameliorating effect and are excellent in the skin beautifying effect.
The present invention has been completed from the above-described viewpoints and an object of the present invention is to provide a photoaging inhibitor comprising a triterpenoid compound which is highly safe and excellent in photoaging inhibiting effect and another object of the present invention is to provide a skin-care preparation which is excellent in the skin beautifying effect such as preventing and ameliorating wrinkled skin and the like.
As a result of intensive investigation with a view to solving the above-described problems, the present inventors have found that among triterpenoid derivatives which derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of ursolic, oleanolic or betulic acid, those which derived by substituting a functional group having an aromatic ring for at least one of the above-described hydrogen atoms (hereafter, sometimes referred to as xe2x80x9caromatic compound derivative of triterpenoidxe2x80x9d) and salts thereof have a physiological activity by at least 10 times as potent in the effect of inhibiting or ameliorating photoaging of skin as triterpenoids such as ursolic acid, oleanolic acid, and betulic acid, and their aliphatic acyl derivatives and aliphatic ester derivatives hitherto reported and further that skin-care preparations containing the above-described aromatic compound derivative of triterpenoid and/or salts thereof are excellent in the skin beautifying effect such as preventing and ameliorating wrinkled skin and the like, thus completing the present invention.
That is, the present invention provides a photoaging inhibitor comprising one or more compounds selected from triterpenoid derivatives and salts thereof, wherein the triterpenoid derivatives are derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of ursolic, oleanolic or betulic acid, wherein at least one of the functional groups is a functional group having an aromatic ring.
As the compound which can be used as the photoaging inhibitor of the present invention is specifically those in which the functional group having an aromatic ring is a group represented by general formula (I) below when it is a substituent group for the hydrogen atom in the carboxyl group at the 28-position, or a group represented by general formula (I) or (II) below when it is a substituent group for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position: 
wherein, in the above formula (I), R1 represents a substituted or unsubstituted aromatic ring , and R2 represents a hydrogen atom or a substituted or unsubstituted aromatic ring, 
wherein, in the above formula (II), R3 represents a substituted or unsubstituted aromatic ring, and n represents 0 or an integer of up to 2.
More specific compounds include those triterpenoid derivatives and salts thereof, wherein in the general formula (I), the R1 represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group, or a naphthyl group and R2 represents a hydrogen atom or a phenyl group, and the R3 in the general formula (II) represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group, or a naphthyl group.
Further, the present invention provides a skin-care preparation containing one or more compounds selected from triterpenoid derivatives and salts thereof, wherein the triterpenoid derivatives are derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of ursolic, oleanolic or betulic acid, wherein at least one of the functional groups is a functional group having an aromatic ring. The aromatic compound derivative of the triterpenoids and/or salts thereof to be contained in the skin-care preparation specifically include compounds similar to the aromatic compound derivative of the triterpenoids and/or salts thereof that constitute the above-described photoaging inhibitor. A specific example of the content of the aromatic compound derivative of the triterpenoids and/or salts thereof in the skin-care preparation of the present invention is from 0.0001 to 10% by weight based on the total amount of the preparation.
Hereafter, the present invention will be described in detail. First, the photoaging inhibitor of the present invention will be explained.
(1) Photoaging Inhibitor of the Present Invention
The photoaging inhibitor of the present invention comprise one or more compounds selected from triterpenoid derivatives and salts thereof, wherein the triterpenoid derivatives are derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of ursolic, oleanolic or betulic acid, wherein at least one of the functional groups is a functional group having an aromatic ring.
Ursolic acid, oleanolic acid, and betulic acid, which serve as a starting material for triterpenoid derivatives used in the photoaging inhibitor of the present invention are compounds having respective structures shown in sequence as below, are each a substance belonging to triterpenoid and widely distribute in the plant kingdom. 
These three triterpenoids can be easily extracted from plants with generally used organic solvents such as alcohols, e.g., methanol, ethanol, etc. However, ursolic acid, oleanolic acid, and betulic acid used in the present invention are not limited to the type of plants from which they have been originated nor to the method by which they have been extracted from plants. Further, in addition to extraction from plants, the triterpenoids can be produced by chemical synthesis and there is no limitation to use of the triterpenoids obtained thereby. Therefore, any suitable methods may be selected for the production method of producing the triterpenoids used as a starting material for the photoaging inhibitor of the present invention taking into consideration economy, safety and the like. Alternatively, commercially available chemicals may be used as a starting material for the photoaging inhibitor of the present invention; for example, ursolic, oleanolic, and betulic acids are commercially available from Tokyo Kasei, Co., Ltd., etc., Wako Pure Chemical Industries, Ltd., etc., and Aldrich Co., etc., respectively.
The triterpenoid derivatives used in the present invention have the structures which are derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of the above-mentioned three triterpenoids, wherein at least one of the functional groups is a functional group having an aromatic ring. More specifically, the triterpenoid derivatives used in the present invention include those triterpenoid derivatives derived by substituting a functional group having an aromatic ring for the hydrogen atom in the carboxyl group at the 28-position and/or the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid; those triterpenoid derivatives derived by substituting an aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position and by substituting a functional group having an aromatic ring for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid; and those triterpenoid derivatives derived by substituting an aliphatic functional group for the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position and by substituting a functional group having an aromatic ring for the hydrogen atom of the carboxyl group at the 28-position of ursolic, oleanolic or betulic acid.
The triterpenoid derivatives as described above can be used in the present invention. However, among the triterpenoid derivatives, as for the triterpenoid derivatives having the structure which are derived by substituting a functional group having an aromatic ring for at least the hydrogen atom in the carboxyl group at the 28-position, the substituting functional group for the hydrogen atom in the carboxyl group at the 28-position is preferably a group represented by general formula (I) above, while as for the triterpenoid derivatives having the structure which are derived by substituting a functional group having an aromatic ring for at least the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position, the substituting functional group for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position is preferably a group represented by general formulae (I) or (II). Further, as for the triterpenoid derivatives having the structure which are derived by unsubstituting any functional group or substituting an aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position, and by substituting a functional group having an aromatic ring for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position, the substituting functional group for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position is preferably a group represented by general formula (II) above. These triterpenoid derivatives can be said to be excellent in the effect of preventing or ameliorating the photoaging of skin.
Here, in general formula (I), R1 represents a substituted or unsubstituted aromatic ring, and R2 represents a hydrogen atom or a substituted or unsubstituted aromatic ring and, hence, when the group represented by general formula (I) is used as the above-described substituting group in the triterpenoid derivatives, the group which connects the triterpenoid radical to the aromatic ring is a methylene group or a methyne group. However, replacing the connecting group by an alkylene group or alkenyl group having two or more carbon atoms may result in insufficient photoaging preventing effect. Further, in the present invention, it is preferred that in general formula (I), R1 represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group, or a naphthyl group, and R2 represents a hydrogen atom or a phenyl group.
Also, in general formula (II), R3 represents a substituted or unsubstituted aromatic ring. In the present invention, R3 preferably represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group, or a naphthyl group. As stated above, enumerated are preferred specific examples of the group having an aromatic ring represented by general formula (I) or (II). In this manner, in the present invention, the aromatic rings are preferably those having a ring number of 1 or 2.
Among the triterpenoid derivatives used in the present invention, in those triterpenoid derivatives which are derived by substituting a functional group having an aromatic ring for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position and by substituting an aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position of ursolic, oleanolic or betulic acid, examples of the aliphatic functional group include an alkyl group, an alkenyl group, an alkylene group and the like. As for the triterpenoid derivatives used in the present invention, the aliphatic functional group is preferably an alkyl group and further it is preferred that the alkyl group has 1 to 20 carbon atoms, particularly 8 to 20 carbon atoms, from the viewpoint of safety and ease of handling. The alkyl group may be straight or branched chain or cyclic.
Further, in those triterpenoid derivatives which are derived by substituting a functional group having an aromatic ring for the hydrogen atom in the carboxyl group at the 28-position and by substituting an aliphatic functional group for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid, examples of the aliphatic functional group include an alkyl group, an alkenyl group, an alkylene group, an aliphatic acyl group and the like. As for the triterpenoid derivatives used in the present invention, the aliphatic functional group is preferably an alkyl group or an alkylacyl group and further it is preferred that the alkyl portions of them have 1 to 20 carbon atoms, particularly 8 to 20 carbon atoms, similarly to the above. These alkyl portions may be of a straight or branched chain or cyclic.
The triterpenoid derivatives used in the present invention can be produced by commonly used methods, for example, by a method which uses as a starting material ursolic, oleanolic or betulic acid or a triterpenoid derivative obtained by substituting the aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position or the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid, and allows the starting material to react with an aromatic compound by a synthetic reaction in which the hydrogen atom in the carboxyl group at the 28-position and/or the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position contribute(s) to the reaction, more specifically by a method in which the carboxyl group at the 28-position is esterified with a halogenated aromatic compound, a method in which the hydroxyl group bonded to the carbon atom at the 3-position is etherified with an aromatic alcohol or esterified with an aromatic carboxylic acid, or the like.
To produce the triterpenoid derivatives used as the above-described starting material, which are obtained by substituting the aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position or the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid, there can be cited a method in which the carboxyl group at the 28-position of ursolic, oleanolic or betulic acid is esterified with an aliphatic compound, a method in which the hydroxyl group bonded to the carbon atom at the 3-position of the acid is etherified or esterified with an aliphatic compound, and the like. The etherification and esterification can be performed in the same manner as commonly used methods. For example, esterification through the carboxyl group at the 28-position can be performed in the same manner as the esterification reaction of ordinary carboxylic acids, for example, by allowing the above-described triterpenoid to react with a chlorinating agent such as thionyl chloride in a suitable solvent such as chloroform in the presence of a base such as triethylamine to produce a chloride of the triterpenoid, and allowing the chloride to react with a desired aliphatic alcohol such as methanol, ethanol, isopropyl alcohol, butanol, 2-ethylhexyl alcohol, oleyl alcohol, cetanol, stearyl alcohol, etc. in the presence of a base such as triethylamine.
More specifically illustrating the production method of producing the triterpenoid derivatives used in the present invention, for example, in the case where ursolic, oleanolic or betulic acid or the triterpenoid derivative which is obtained by substituting the aliphatic functional group for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of the acid is used as a starting material in order to produce the triterpenoid derivative having the structure which is derived by substituting the group represented by general formula (I) above for at least the hydrogen atom in the carboxyl group at the 28-position of the starting material, there can be cited preferably a method in which the above-described starting material is allowed to react in the presence of a polar solvent such as acetone with a desired reagent obtained by adding bromine or chlorine to a methylene or methyne group which is bonded to the aromatic ring.
Also, in the case where ursolic, oleanolic or betulic acid or the triterpenoid derivative which is obtained by substituting the aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position of the acid is used as a starting material in order to produce the triterpenoid derivative having the structure which is derived by substituting the group represented by general formula (II) above for at least the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of the starting material, there can be cited preferably a method in which the above-described starting material is allowed to react in the presence of a non-polar solvent such as tetrahydrofuran and a base such as triethylamine with a desired reagent obtained by brominating or chlorinating the carboxyl group of an aromatic carboxylic acid having the structure in which a carboxyl group is bonded to an aromatic ring through an alkylene group having 0 to 2 carbon atoms.
Further, among the triterpenoid derivatives used in the present invention, in those which are derived by substituting the functional group having the aromatic ring for the hydrogen atom in the carboxyl group at the 28-position and by substituting the aliphatic functional group for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid, or in those which are derived by substituting the functional group having the aromatic ring for the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position and by substituting the aliphatic functional group for the hydrogen atom in the carboxyl group at the 28-position of ursolic, oleanolic or betulic acid, there can be used a production method in which the substitution of ursolic, oleanolic or betulic acid with an aromatic functional group is performed before the substitution with an aliphatic functional group is carried out.
Besides the thus produced triterpenoid derivatives used as a photoaging inhibitor, the salts of the triterpenoid derivatives may be employed. The salts of the triterpenoid derivatives may include an ammonium salt, an alkali metal salt, an organic amine salt and the like, which are obtained by reacting the triterpenoid derivatives with inorganic or organic bases.
In addition, the triterpenoid derivatives which are derived by substituting the functional group for the hydrogen atom in the carboxyl group at the 28-position and/or the hydrogen atom in the hydroxyl group bonded to the carbon atom at the 3-position of ursolic, oleanolic or betulic acid, wherein at least one of the functional groups is the functional group having the aromatic ring, and salts thereof are very stable and their preparations do not cause changes with lapse of time such as discoloration, disodoration, and deactivation by decomposition, so that they can be blended in various preparation formulations with stability and ease.
Next, the skin-care preparations of the present invention will be described.
(2) Skin-care Preparations of the Present Invention
The skin-care preparations of the present invention comprises one or more of triterpenoid derivatives which are derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of ursolic, oleanolic or betulic acid, wherein at least one of the functional groups is a functional group having an aromatic ring, and salts thereof.
The triterpenoid derivatives which are derived by substituting a functional group for a hydrogen atom in a carboxyl group at the 28-position and/or a hydrogen atom in a hydroxyl group bonded to a carbon atom at the 3-position of ursolic, oleanolic or betulic acid, wherein at least one of the functional groups is a functional group having an aromatic ring, and salts thereof (hereinafter referred as xe2x80x9ctriterpenoid compoundxe2x80x9d) comprised in the skin-care preparations of the present invention are as described in (1) above and the triterpenoid compounds similar to them can be used in the skin-care preparations of the present invention.
A blending amount of the triterpenoid compound in the skin-care preparations of the present invention is preferably from 0.0001 to 10% by weight, more preferably from 0.001 to 1% by weight, based on the total amount of the preparation. If the blending amount of the triterpenoid compound to the skin-care preparation is less than 0.0001% by weight, the skin beautifying effect like an effect of ameliorating the skin condition such as wrinkled skin may be insufficient while use of the blending amount of above 10% by weight may result in failure of giving the effect which corresponds to an increment in the proportion.
The type of formulation of the preparation of the present invention is not limited particularly but there can be cited, for example, cream, emulsion, oil, lotion, pack, aqueous gel, oil gel and ointment. From the viewpoint of absorption, cream, emulsion, oil and the like are more preferred formulations. These skin-care preparations can be produced in the same manner as conventional skin-care preparations except that the triterpenoid compound is selected and blended appropriately depending on the type of formulation.
In addition to the triterpenoid compound, the skin-care preparations of the present invention may contain one or more of suitably selected ones from various components usually used in skin-care preparations, that is, hydrocarbons such as liquid paraffin, vaseline, and squalane; esters such as isopropyl myristate (IPM), synthetic spermaceti, jojoba oil, and carnauba wax; animal and plant fats and oils such as olive oil and beef tallow; higher alcohols such as cetanol and stearyl alcohol; higher fatty acids such as stearic acid and oleic acid; surfactants including anionic surfactants such as sodium lauryl sulfate and alkylsulfosuccinic acid ester, cationic surfactants such as quaternary alkylamine salt, nonionic surfactants such as fatty acid monoglyceride and polyoxyethylene hardened castor oil, and amphoteric surfactants such as alkylbetaine; polyvalent alcohols such as glycerol and propylene glycol; lower alcohols such as ethanol and propanol; preservatives such as paraben and chlorhexidine gluconate; ultraviolet-absorbing agents such as paraaminobenzoic acid derivative and benzophenone derivative; antioxidants such as vitamin E and butylhydroxytoluene; thickeners such as gum arabic and carboxyvinylpolymer; humectants such as polyethylene glycol; pH adjusting agents such as citric acid salt and acetic acid salt; powders such as titanium oxide, silica gel, and talc; perfumes; dyes; medicinal components in response to various objects such as hyaluronic acid, placenta extract, ginseng extract, vitamins, and sterol glucoside; and the like.